HUMAN RETROVIRUS: A STORY OF SClENTlFlC DISCOVERY Contents Acknowledgments Prologue 1 SOME HISTORY BEHIND THE STORY 1. Becorning a Physician, Becoming a Scientist 13 2. The National Institutes of Health and the Laboratory of Tumor Ce11 Biology 26 3. Microscopic Intruders 44 I1 THE DISCOVERY OE CANCER-CAUSING RETROVIRUSES IN HUMANS 4. The Story of Retroviruses and Cancer: From Poultry to People 59 5. Success, Defeat, Success 82 6. Discovery of a Cancer Virus: The First Human Retrovirus 99 7. Discovery of the Second Human Retrovirus (and How the HTLVs Produce Disease) 116 viii CONTENTS I11 THE DISCOVERY OF A THIRD HUMAN RETROVIRUS: THE AIDS VIRUS 8. A Single Disease with a Single Cause 127 9. Breaking Through: "We Know How to Work with This Kind of Virus" 163 10. Making Progress, Making Sense: The Period of Intense Discovery 181 11. The Blood Test Patent Suit: Rivalry and Resolution 205 IV A SCIENTIST'S LOOK AT THE SCIENCE AND POLITICS OF AIDS 12. The Alarm 13. How the AIDS Virus Works 14. Kaposi's Sarcoma: A Special Tumor of AIDS 15. About Causes of Disease (and, in Particular, Why HIV 1s the Cause of AIDS) 16. What We Can Do About AIDS and the AIDS Virus Epilogue Name Index Subject Index X ACKNOWLEDGMENTS Anna Mazzuca, our super editorial secretary, gave me much &- hour assistance. Without her dedicated help none of this Story would have gone past its inception. I am grateful to my farnily for help and understanding during the whole process, particularly on those weekends when a free moment from work turned out to be a few days at home with my editord. .,Theperiod of writing this book completely overlapped with a time of considerable pressure and unusual Stress from other sources. I was most fortunate in this Same period to have personal Support and friendship from the people I have already mentioned, as well as from Robert Gray, Joseph Onek, Robert-Charrow, Wayne Pines, and Sena- tor Birch Bayh (all of Washington, D.C.), and Drs. Dani Bolognesi, Daniel Zagury, Howard Temin, Odile Picard, Jacques Leibowitch, Samuel Broder, Tony Fauci, Kay Jamison, Richard Wyatt, Alec Whyte, Harvey Resnik, Robert Ting, Tony Kontaratos, Takis Papas, Stu Aaronson, Jeffrey Schlom, Hilary Koprowski, Courtenay Bar- tholomew, Maurice Hilleman, and Bob Redfield. To all of them and many other European and Israeli friends, I am deeply grateful. It is impossible to acknowledge properly here tfie many medical scientists of the past and present whose work set the Stage for or aided mine and my colleagues', the many mentors who have directly and indirectly influenced my own work and thinking, and my many co- workers-senior and junior-who carried out most of the work I describe in this book. I tried to bring them into this story when the opportunity presented itself, but in no case could I do proper justice to their essential roles. I hope they will exnise my shortcomings. Finally, I was very lucky in the book world's wheel of fortune to have drawn the outstanding and dedicated staff of Basic Books, partic- ularly Susan Rabiner, my senior editor, who made many contribu- tions, including many hours of stimulating discussions and numerous invaluable recommendations which really in the end made me able to produce this book. Bill Newlin was the initial editor but left for a new position in Hong Kong about one-third of the way to completion; his role during that period was no less important. I thank both of them and am happy that new friendships were made. I thank Linda Car- hone, copy editor, for her patience with my mistakes and for her expert help. I hope together we have accomplished some of our objectives. Prologue In marshy places EZttle animals multiply, which tbe eye can- not see but tbey . , entw the body thvougb mouth and nose and may cause grave disease. -Marcus Varro TheRoman writer who made this observation over two rhousand years ago was, I imagine, the first Person to make a connec- tim between disease and what centuries later we came to call mi- crobes. Though we now know that microbes have been linked with human biology for as long as we have been on earth, it was almost two millennia after Varro's astute guess that scientists had their first glhpse of these organisms and begv to record their activity. Fw-reaching scientific advances inevitably await major technologi- cal breakthroughs, and it wasn't until 1677 that the Dutchman Anton van Leeuwenhoek perfected a lens powerful enough to allow us our bst look into the world of microbes. Though Leeuwenhoek's lens- grinding techniques opened this new world to human investigation, aeither he nor any of the many scientists of his time who used his hsto study microbes made the connection to human disease. A cenmry later, the Italian scientist Lazzaro Spallanaani demonstrated 2 PROLOGUE that microbes reproduce themselves and that it is their growth that causes meat to decay. Yet even he did not suggest that they might be involved in human disease. That was left to an amateur Italian scientist named Augustino Bassi (whom Barry Wood, the eminent infectious disease expert, called the founder of medical microbiology). Bassi first identified a microbe (in this case, a fungus) as the cause of a certain disease of silkworms and then offered the startling proposition that smallpox, cholera, and other human diseases are also caused by microbes. Around 1839, the Ger- man physician Johann Schönlein linked a human disease (of the skin) to a microbe (also a fungus). Soon thereafter, the marvelously analyti- cai thinker Roben Koch of Germany and the passionate, equally brilliant Louis Pasteur of France made major advances that would alter the history of microbiology and, ultimately, of biology itself. Working separately, Koch and Pasteur (and the schools that arose around them) discovered the microbial causes of the major infectious diseases of their time. In 1865, Pasteur identified in silkworms the first disease caused by a protozoan; in 1876, Koch was the first to convict a specific bacterial agent as the cause of a specific disease-anthrax of sheep, and in 1882, he was the first to describe and isolate the cause of a human bacteriul disease-tuberculosis. From 1875 to 1895, Koch established his famous postulates for identifying causal agents of dis- ease. He and the German school found bacterial causes for many other diseases. During the Same twenty-year Span, Pasteur discovered the principles of the vaccine. The discovery of viruses soon followed. The plant virus known as tobacco mosaic virus was the first m be found-by the Russian biolo- gist Ivanovsky in 1892 and, independently and with more accompany- ing insight, by Beijerinck in Holland in 1899. In 1898, the German bacteriologist Friedtich Löffler identified the first animal virus, the foot-and-mouth viral disease of cattle. The United States made its historical entry into microbiology in 1900, when the army surgeon Walter Reed and his group, by establishing the cause of yellow fever, were the first to discover a disease-causing virus in humans. This was the romantic era of biomedical science. The personal Courage of these scientists and their persistence in the face of almost continual frustration and disappointment benefited from an increased understmding of and reliance upon the scientific method. In time their efforts, though often excessively zealous and relying upon PROLOGUE human experimentation f& riskier than anything we would allow today, led to the elucidation of the microbial causes and modes of transmission of many of the known infectiops diseases. The age of empirical antimicrobial therapy followed Paul Ehrlich's discovery in 1909 of his "magic bullet," Salvarsan, to attack the syphilis spirochete.* These discoveries and treatment breakthroughs fueled the imagination of science writers, novelists, and screenwriters, as well as providing the raw material for the classic work of popular science writing of that time-Paul de Kruif s Mzcrobe Hunters (1926). For decades to come, this book would inspire many young readers to follow a career in science. While de Kruif was writing about the romantic age of biomedical discovery, he probably knew little-if anything-of two pioneering experiments that would in time help refine our notions of infectious disease. These experiments, ignored by most scientists, were the first to suggest that certain animal Cancers appeared to be communicable. The first of these experiments was conducted at the turn of the century by two Danish researchers, Oluf Bang and Vilhelm Ellerman, who found that filtered extracts of chicken leukemic cells inoculated into other chickens reproduced leukemia. The culprit in the extract was not isolated at the time, but its ability, whatever it was, to move through certain filters suggested that it was smaller than the smallest bacteria then known-in other words, it was probably in the category of viruses. A few years later, in 1911, Peyton Rous in New York isolated a 1 microbe from a chicken with a sarcoma, a Cancer of muscle tissue. He, too, showed that this agent could reproduce its disease when injected into another chicken. At the time these experiments were being conducted and for sev- erd decades thereafter, no one, not even the researchers themselves, knew that these experiments were the first to study the effects on ; animals of a class of infectious agent that would play a profound role in infectious disease of the late twentieth century. These pioneering I *The magic bullet was also given the name "606," from its number in Ehrlich's sequence of experiments. (The popular 1940 movie DY.Ehrlicb'J Mugic Bullet, starring Edward G.